Sir Peter MacCallum Department of Oncology - Research Publications

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    Long-Term Outcomes of TROG 13.01 SAFRON II Randomized Trial of Single- Versus Multifraction Stereotactic Ablative Body Radiotherapy for Pulmonary Oligometastases
    Siva, S ; Sakyanun, P ; Mai, T ; Wong, W ; Lim, A ; Ludbrook, J ; Bettington, C ; Rezo, A ; Pryor, D ; Hardcastle, N ; Kron, T ; Higgs, B ; Le, H ; Skala, M ; Gill, S ; Eade, T ; Awad, R ; Sasso, G ; Vinod, S ; Montgomery, R ; Ball, D ; Bressel, M (LIPPINCOTT WILLIAMS & WILKINS, 2023-07-01)
    Clinical trials frequently include multiple end points that mature at different times. The initial report, typically based on the primary end point, may be published when key planned co-primary or secondary analyses are not yet available. Clinical Trial Updates provide an opportunity to disseminate additional results from studies, published in JCO or elsewhere, for which the primary end point has already been reported.In a randomized phase II clinical trial, the Trans Tasman Radiation Oncology Group compared single- versus multifraction stereotactic ablative body radiotherapy (SABR) in 90 patients with 133 oligometastases to the lung. The study found no differences in safety, efficacy, systemic immunogenicity, or survival between arms, with single-fraction SABR picked as the winner on the basis of cost-effectiveness. In this article, we report the final updated survival outcome analysis. The protocol mandated no concurrent or post-therapy systemic therapy until progression. Modified disease-free survival (mDFS) was defined as any progression not addressable by local therapy, or death. At a median follow-up of 5.4 years, the 3- and 5-year estimates for overall survival (OS) were 70% (95% CI, 59 to 78) and 51% (95% CI, 39 to 61). There were no significant differences between the multi- and single-fraction arms for OS (hazard ratio [HR], 1.1 [95% CI, 0.6 to 2.0]; P = .81). The 3- and 5-year estimates for disease-free survival were 24% (95% CI, 16 to 33) and 20% (95% CI, 13 to 29), with no differences between arms (HR, 1.0 [95% CI, 0.6 to 1.6]; P = .92). The 3- and 5-year estimates for mDFS were 39% (95% CI, 29 to 49) and 34% (95% CI, 24 to 44), with no differences between arms (HR, 1.0 [95% CI, 0.6 to 1.8]; P = .90). In this patient population, where patients receive SABR in lieu of systemic therapy, one-in-three patients are alive without disease in the long term. There were no differences in outcomes by fractionation schedule.
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    Early circulating tumor DNA dynamics at the commencement of curative-intent radiotherapy or chemoradiotherapy for NSCLC
    MacManus, M ; Kirby, L ; Blyth, B ; Banks, O ; Martin, OA ; Yeung, MM ; Plumridge, N ; Shaw, M ; Hegi-Johnson, F ; Siva, S ; Ball, D ; Wong, SQ (ELSEVIER IRELAND LTD, 2023-11)
    BACKGROUND: The kinetics of circulating tumor DNA (ctDNA) release following commencement of radiotherapy or chemoradiotherapy may reflect early tumour cell killing. We hypothesised that an increase in ctDNA may be observed after the first fraction of radiotherapy and that this could have clinical significance. MATERIALS AND METHODS: ctDNA analysis was performed as part of a prospective, observational clinical biomarker study of non-small cell lung cancer (NSCLC) patients, treated with curative-intent radiotherapy or chemoradiotherapy. Blood was collected at predefined intervals before, during (including 24 h after fraction 1 of radiotherapy) and after radiotherapy/chemoradiotherapy. Mutation-specific droplet digital PCR assays used to track ctDNA levels during and after treatment. RESULTS: Sequential ctDNA results are available for 14 patients with known tumor-based mutations, including in EGFR, KRAS and TP53, with a median follow-up of 723 days (range 152 to 1110). Treatments delivered were fractionated radiotherapy/chemoradiotherapy, in 2-2.75 Gy fractions (n = 12), or stereotactic ablative body radiotherapy (SABR, n = 2). An increase in ctDNA was observed after fraction 1 in 3/12 patients treated with fractionated radiotherapy with a complete set of results, including in 2 cases where ctDNA was initially undetectable. Neither SABR patient had detectable ctDNA immediately before or after radiotherapy, but one of these later relapsed systemically with a high detected ctDNA concentration. CONCLUSIONS: A rapid increase in ctDNA levels was observed after one fraction of fractionated radiotherapy in three cases. Further molecular characterization will be required to understand if a "spike" in ctDNA levels could represent rapid initial tumor cell destruction and could have clinical value as a surrogate for early treatment response and/or as a means of enriching ctDNA for mutational profiling.
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    Modern paradigms for prostate cancer detection and management
    Williams, ISC ; McVey, A ; Perera, S ; O'Brien, JS ; Kostos, L ; Chen, K ; Siva, S ; Azad, AA ; Murphy, DG ; Kasivisvanathan, V ; Lawrentschuk, N ; Frydenberg, M (WILEY, 2022-10-17)
    Early detection and management of prostate cancer has evolved over the past decade, with a focus now on harm minimisation and reducing overdiagnosis and overtreatment, given the proven improvements in survival from randomised controlled trials. Multiparametric magnetic resonance imaging (mpMRI) is now an important aspect of the diagnostic pathway in prostate cancer, improving the detection of clinically significant prostate cancer, enabling accurate localisation of appropriate sites to biopsy, and reducing unnecessary biopsies in most patients with normal magnetic resonance imaging scans. Biopsies are now performed transperineally, substantially reducing the risk of post-procedure sepsis. Australian-led research has shown that prostate-specific membrane antigen (PSMA) positron emission tomography/computed tomography (PET/CT) has superior accuracy in the staging of prostate cancer than conventional imaging (CT and whole-body bone scan). Localised prostate cancer that is low risk (International Society for Urological Pathology [ISUP] grade 1, Gleason score 3 + 3 = 6; and ISUP grade group 2, Gleason score 3 + 4 = 7 with less than 10% pattern 4) can be offered active surveillance, reducing harms from overtreatment. Prostatectomy and definitive radiation remain the gold standard for localised intermediate and high risk disease. However, focal therapy is an emerging experimental treatment modality in Australia in carefully selected patients. The management of advanced prostate cancer treatment has evolved to now include several novel agents both in the metastatic hormone-sensitive and castration-resistant disease settings. Multimodal therapy with androgen deprivation therapy, additional systemic therapy and radiotherapy are often recommended. PSMA-based radioligand therapy has emerged as a treatment option for metastatic castration-resistant prostate cancer and is currently being evaluated in earlier disease states.
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    Impact of Prostate-specific Membrane Antigen Positron Emission Tomography/Computed Tomography in the Management of Oligometastatic Renal Cell Carcinoma
    Udovicich, C ; Callahan, J ; Bressel, M ; Ong, WL ; Perera, M ; Tran, B ; Azad, A ; Haran, S ; Moon, D ; Chander, S ; Shaw, M ; Eapen, R ; Goad, J ; Lawrentschuk, N ; Murphy, DG ; Hofman, M ; Siva, S (ELSEVIER, 2022-10)
    BACKGROUND: Prostate-specific membrane antigen (PSMA) is overexpressed in the neovasculature of renal cell carcinoma (RCC). However, there remains limited evidence regarding the use of PSMA positron emission tomography/computed tomography (PET/CT) in RCC. OBJECTIVE: To assess the impact of PSMA PET/CT in the management of metastatic RCC. DESIGN SETTING AND PARTICIPANTS: This was a retrospective review of patients who underwent PSMA PET/CT from 2014 to 2020 for restaging or suspected metastatic RCC in a tertiary academic setting. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Management plans before and after PSMA PET/CT were recorded. Impact was classified as high (change of treatment intent, modality, or site), medium (change in treatment method), or low. Secondary outcomes included the patient-level detection rate, PSMA PET/CT parameters, sensitivity, and comparison to CT and, if available, fluorodeoxyglucose (FDG) PET/CT. RESULTS AND LIMITATIONS: Sixty-one patients met the inclusion criteria, of whom 54 (89%) had clear cell RCC. PSMA-positive disease was detected in 51 patients (84%). For 30 patients (49%) there was a change in management due to PSMA PET/CT (high impact, 29 patients, 48%). In 15 patients (25%), more metastases were detected on PSMA PET/CT than on CT. The sensitivity of combined PSMA PET/CT and diagnostic CT was 91% (95% confidence interval 77-98%). In a subcohort of 40 patients, the detection rate was 88% for PSMA and 75% for FDG PET/CT (p = 0.17). The maximum standardised uptake value (SUVmax) was higher for PSMA than for FDG PET/CT (15.2 vs 8.0; p = 0.02). Limitations include selection bias due to the retrospective design, and a lack of corresponding histopathology for all patients. CONCLUSIONS: PSMA PET/CT is a promising imaging modality in metastatic RCC and led to a change in management in 49% of patients. PSMA PET/CT detected additional metastases compared to CT in 25% of patients and registered a significantly higher SUVmax than FDG PET/CT. Prospective studies are required to further define its role. PATIENT SUMMARY: We report on a group of patients undergoing a new type of imaging for suspected advanced kidney cancer, called PSMA PET/CT. This imaging changed the management plan in 49% of the patients. PSMA PET/CT detected metastases in 84% of our patients and detected more metastases than computed tomography imaging in 25%.
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    From minimally to maximally invasive; VT ablation in the setting of mechanical aortic and mitral valves
    Hawson, J ; Kalman, J ; Goldblatt, J ; Anderson, RD ; Watts, T ; Hardcastle, N ; Siva, S ; Kumar, S ; Lee, G (WILEY, 2022-09)
    Double mitral and aortic mechanical valves present an access challenge when planning a ventricular tachycardia (VT) ablation. In this case report, we describe a patient who was considered for stereotactic ablative radiotherapy but was unable to proceed due to unfavorable anatomy making them at high risk of fistula formation. The patient went on to have an endocardial VT ablation via mini-thoracotomy and transapical access without complication. This case highlights the need for careful consideration when planning treatment for patients with double mechanical valves.
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    Avelumab Combined with Stereotactic Ablative Body Radiotherapy in Metastatic Castration-resistant Prostate Cancer: The Phase 2 ICE-PAC Clinical Trial
    Kwan, EM ; Spain, L ; Anton, A ; Gan, CL ; Garrett, L ; Chang, D ; Liow, E ; Bennett, C ; Zheng, T ; Yu, J ; Dai, C ; Du, P ; Jia, S ; Fettke, H ; Abou-Seif, C ; Kothari, G ; Shaw, M ; Parente, P ; Pezaro, C ; Tran, B ; Siva, S ; Azad, AA (ELSEVIER, 2022-03)
    BACKGROUND: Immune checkpoint inhibitor monotherapy in metastatic castration-resistant prostate cancer (mCRPC) has produced modest results. High-dose radiotherapy may be synergistic with checkpoint inhibitors. OBJECTIVE: To evaluate the efficacy and safety of the PD-L1 inhibitor avelumab with stereotactic ablative body radiotherapy (SABR) in mCRPC. DESIGN, SETTING, AND PARTICIPANTS: From November 2017 to July 2019, this prospective phase 2 study enrolled 31 men with progressive mCRPC after at least one prior androgen receptor-directed therapy. Median follow-up was 18.0 mo. INTERVENTION: Avelumab 10 mg/kg intravenously every 2 wk for 24 wk (12 cycles). A single fraction of SABR (20 Gy) was administered to one or two disease sites within 5 d before the first and second avelumab treatments. OUTCOMES MEASUREMENTS AND STATISTICAL ANALYSIS: The primary endpoint was the disease control rate (DCR), defined as a confirmed complete or partial response of any duration, or stable disease/non-complete response/non-progressive disease for ≥6 mo (Prostate Cancer Clinical Trials Working Group 3-modified Response Evaluation Criteria in Solid Tumours version 1.1). Secondary endpoints were the objective response rate (ORR), radiographic progression-free survival (rPFS), overall survival (OS), and safety. DCR and ORR were calculated using the Clopper-Pearson exact binomial method. RESULTS AND LIMITATIONS: Thirty-one evaluable men were enrolled (median age 71 yr, 71% with ≥2 prior mCRPC therapy lines, 81% with >5 total metastases). The DCR was 48% (15/31; 95% confidence interval [CI] 30-67%) and ORR was 31% (five of 16; 95% CI 11-59%). The ORR in nonirradiated lesions was 33% (four of 12; 95% CI 10-65%). Median rPFS was 8.4 mo (95% CI 4.5-not reached [NR]) and median OS was 14.1 mo (95% CI 8.9-NR). Grade 3-4 treatment-related adverse events occurred in six patients (16%), with three (10%) requiring high-dose corticosteroid therapy. Plasma androgen receptor alterations were associated with lower DCR (22% vs 71%, p = 0.13; Fisher's exact test). Limitations include the small sample size and the absence of a control arm. CONCLUSIONS: Avelumab with SABR demonstrated encouraging activity and acceptable toxicity in treatment-refractory mCRPC. This combination warrants further investigation. PATIENT SUMMARY: In this study of men with advanced and heavily pretreated prostate cancer, combining stereotactic radiotherapy with avelumab immunotherapy was safe and resulted in nearly half of patients experiencing cancer control for 6 months or longer. Stereotactic radiotherapy may potentially improve the effectiveness of immunotherapy in prostate cancer.
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    Role of PSMA PET-guided metastases-directed therapy in oligometastatic recurrent prostate cancer
    Alberto, M ; Yim, A ; Papa, N ; Siva, S ; Ischia, J ; Touijer, K ; Eastham, JA ; Bolton, D ; Perera, M (FRONTIERS MEDIA SA, 2022-08-18)
    Oligometastatic prostate cancer (OMPC) has been proposed as an intermediary state between localised disease and widespread metastases, with varying definitions including 1, 3, or ≤5 visceral or bone metastasis. Traditional definitions of OMPC are based on staging with conventional imaging, such as computerised tomography (CT) and whole-body bone scan (WBBS). Novel imaging modalities such as prostate-specific membrane antigen positron emission tomography (PSMA PET) have improved diagnostic utility in detecting early metastatic prostate cancer (PC) metastases compared with conventional imaging. Specifically, meta-analytical data suggest that PSMA PET is sensitive in detecting oligometastatic disease in patients with biochemical recurrence (BCR) post-radical treatment of PC. Recent trials have evaluated PSMA PET-guided metastases-directed therapy (MDT) in oligometastatic recurrent disease, typically with salvage surgery or radiotherapy (RT). To date, these preliminary studies demonstrate promising results, potentially delaying the need for systemic therapy. We aim to report a comprehensive, multidisciplinary review of PSMA-guided MDT in OMPC. In this review, we highlight the utility of PMSA PET in biochemically recurrent disease and impact of PSMA PET on the definition of oligometastatic disease and outline data pertaining to PSMA-guided MDT.
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    The Emerging Role of Extracranial Stereotactic Ablative Radiotherapy for Metastatic Renal Cell Carcinoma: A Systematic Review
    Le Guevelou, J ; Sargos, P ; Siva, S ; Ploussard, G ; Ost, P ; Gillessen, S ; Zilli, T (ELSEVIER, 2023-01)
    CONTEXT: Although the management of metastatic renal cell carcinoma (mRCC) has been revolutionized by the advent of new systemic agents, still few patients experience a long-term durable response. Stereotactic ablative radiotherapy (SABR) is nowadays commonly used as metastasis-directed therapy (MDT), but limited data exist on how best to implement this strategy as part of a multimodal approach. OBJECTIVE: To evaluate the potential role of extracranial SABR in mRCC and to identify future therapeutic developments of SABR in different disease settings. EVIDENCE ACQUISITION: A systematic review was conducted in May 2022 according to the Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) statement on the PubMed database. Thirty-four studies were selected for inclusion in this systematic review. EVIDENCE SYNTHESIS: SABR has been used with four main goals: (1) eradication of the whole metastatic burden in synchronous and metachronous oligometastatic patients, resulting in a long-term local control (LC) rate of >90% and median progression-free survival (PFS) ranging between 8 and 15 mo; (2) eradication of oligoprogressive lesions, enabling an extension of the duration of the systemic therapy by approximately 9 mo; (3) improvement of the response to systemic therapy in polymetastatic patients, resulting in an overall response rate ranging from 17% to 56%; and (4) cytoreduction in polymetastatic mRCC patients, with LC rates ranging between 71% and 100%, and preservation of the renal function, but unclear PFS and overall survival impact. Overall, the combination of SABR and systemic agents has been associated with overall good tolerance, with grade ≥3 toxicity ranging from 0% to 13%. CONCLUSIONS: Current data highlight the role of SABR as an emerging MDT treatment option in both oligometastatic and oligoprogressive extracranial mRCC, able to ensure long-term disease control and delay the use of next-line systemic therapies. The use of SABR for cytoreduction in the de novo metastatic disease and as an immunological booster in the polymetastatic setting remains investigational and warrants further investigations. PATIENT SUMMARY: Radiotherapy delivered with ablative doses (>6 Gy per fraction) is a promising treatment strategy for patients diagnosed with metastatic renal cell carcinoma. Excellent outcome results have been observed in patients with a limited number of metastases, improving metastasis-free survival by several months. For patients with a few metastases progressing under systemic therapy, radiotherapy allows an extension of the duration of the ongoing therapy by several months.
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    Treatment Time Optimization in Single Fraction Stereotactic Ablative Radiation Therapy: A 10-Year Institutional Experience
    Gaudreault, M ; Yeo, A ; Kron, T ; Hanna, GG ; Siva, S ; Hardcastle, N (ELSEVIER INC, 2022)
    PURPOSE: Stereotactic ablative radiation therapy (SABR) delivered in a single fraction (SF) can be considered to have higher uncertainty given that the error probability is concentrated in a single session. This study aims to report the variation in technology and technique used and its effect on intrafraction motion based on a 10 years of experience in SF SABR. METHODS AND MATERIALS: Records of patients receiving SF SABR delivered at our instruction between 2010 and 2019 were included. Treatment parameters were extracted from the patient management database by using an in-house script. Treatment time was defined as the time difference between the first image acquisition to the last beam off of a single session. The intrafraction variation was measured from the 3-dimensional couch displacement measured after the first cone beam computed tomography (CBCT) acquired during a treatment. RESULTS: The number of SF SABR increased continuously from 2010 to 2019 and were mainly lung treatments. Treatment time was minimized by using volumetric modulated arc therapy, flattening filter-free dose rate, and coplanar field (24 ± 9 min). Treatment time increased as the number of CBCTs per session increased. The most common scenario involved both 2 and 3 CBCTs per session. On the average, a CBCT acquisition added 6 minutes to the treatment time. All treatments considered, the average intrafraction variation was 1.7 ± 1.6 mm. CONCLUSIONS: SF SABR usage increased with time in our institution. The intrafraction motion was acceptable and therefore a single fraction is an efficacious treatment option when considering SABR.
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    Long-Term Outcomes and Genetic Predictors of Response to Metastasis-Directed Therapy Versus Observation in Oligometastatic Prostate Cancer: Analysis of STOMP and ORIOLE Trials
    Deek, MP ; Van der Eecken, K ; Sutera, P ; Deek, RA ; Fonteyne, V ; Mendes, AA ; Decaestecker, K ; Kiess, AP ; Lumen, N ; Phillips, R ; De Bruycker, A ; Mishra, M ; Rana, Z ; Molitoris, J ; Lambert, B ; Delrue, L ; Wang, H ; Lowe, K ; Verbeke, S ; Van Dorpe, J ; Bultijnck, R ; Villeirs, G ; De Man, K ; Ameye, F ; Song, DY ; DeWeese, T ; Paller, CJ ; Feng, FY ; Wyatt, A ; Pienta, KJ ; Diehn, M ; Bentzen, SM ; Joniau, S ; Vanhaverbeke, F ; De Meerleer, G ; Antonarakis, ES ; Lotan, TL ; Berlin, A ; Siva, S ; Ost, P ; Tran, PT (LIPPINCOTT WILLIAMS & WILKINS, 2022-10-10)
    Clinical trials frequently include multiple end points that mature at different times. The initial report, typically based on the primary end point, may be published when key planned co-primary or secondary analyses are not yet available. Clinical Trial Updates provide an opportunity to disseminate additional results from studies, published in JCO or elsewhere, for which the primary end point has already been reported.The initial STOMP and ORIOLE trial reports suggested that metastasis-directed therapy (MDT) in oligometastatic castration-sensitive prostate cancer (omCSPC) was associated with improved treatment outcomes. Here, we present long-term outcomes of MDT in omCSPC by pooling STOMP and ORIOLE and assess the ability of a high-risk mutational signature to risk stratify outcomes after MDT. The primary end point was progression-free survival (PFS) calculated using the Kaplan-Meier method. High-risk mutations were defined as pathogenic somatic mutations within ATM, BRCA1/2, Rb1, or TP53. The median follow-up for the whole group was 52.5 months. Median PFS was prolonged with MDT compared with observation (pooled hazard ratio [HR], 0.44; 95% CI, 0.29 to 0.66; P value < .001), with the largest benefit of MDT in patients with a high-risk mutation (HR high-risk, 0.05; HR no high-risk, 0.42; P value for interaction: .12). Within the MDT cohort, the PFS was 13.4 months in those without a high-risk mutation, compared with 7.5 months in those with a high-risk mutation (HR, 0.53; 95% CI, 0.25 to 1.11; P = .09). Long-term outcomes from the only two randomized trials in omCSPC suggest a sustained clinical benefit to MDT over observation. A high-risk mutational signature may help risk stratify treatment outcomes after MDT.